期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：41
DOI：10.1073/pnas.2107771118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Cancer therapy, such as chemotherapy, induces tumor cell death (“debris”), which can stimulate metastasis. Chemotherapy-generated debris upregulates soluble epoxide hydrolase (sEH) and the prostaglandin E
2 receptor 4 (EP4), which triggers a macrophage-derived storm of proinflammatory and proangiogenic lipid autacoid and cytokine mediators. Although sEH inhibitors and EP4 antagonists are in clinical development for multiple inflammatory diseases, their combined role in cancer is unknown. Here, we show that the synergistic antitumor activity of sEH and EP4 inhibition suppresses hepato-pancreatic tumor growth, without overt toxicity, via macrophage phagocytosis of debris and counterregulation of a debris-stimulated cytokine storm. Thus, stimulating the resolution of inflammation via combined inhibition of sEH and EP4 may be an approach for preventing metastatic progression driven by cancer therapy.
Cancer therapy reduces tumor burden via tumor cell death (“debris”), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E
2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
